Olfactory means useful in the diagnosis and treatment of mood depression

ABSTRACT

A kit of two compositions comprising the same odorants in mixtures of different proportions is used for the measurement of olfactory discrimination capacity in subjects affected by a psychiatric disorder or disease involving mood disturbance, more particularly mood depression.

FIELD OF THE INVENTION

The application relates to olfactory means, more particularly tomixtures of odorants. The means of the application are notably useful inthe diagnosis and in the treatment of psychiatric disorders or diseasesinvolving mood disturbance, more particularly mood depression.

BACKGROUND OF THE INVENTION

Olfaction is known to be closely related to emotional processes andmood. However, little is known about the role of odor impairment inpsychiatric disorders involving mood disturbances, more particularlymood depression. Depressive disorders, depressions, major depressiveepisode(s) and Major Depressive Disorders (MDD) are highly prevalent anddebilitating conditions, associated with significant mortality andextraordinary costs for the society. Selective Serotonin ReuptakeInhibitors (SSRI) and Serotonin and Noradrenalin Reuptake Inhibitors(SNRI) are the most commonly prescribed antidepressant drugs, moreparticularly for the treatment of MDD. Yet, 60% of major depressiveepisodes do not respond adequately and 20-30% of them are resistant toSSRI/SNRI, defining treatment resistant depression.

Pause et al. 2001 (Journal of Psychiatric Research 35: 271-277) relatesto olfactory sensitivity and odor evaluations in a homogenous sample ofunipolar depressive patients compared to healthy control subjects.Olfactory sensitivity is determined by a detection test that uses serialdilutions of propanediol. Odor evaluations are subjective ratings ofodor valence and intensity performed with pure odorants. The pureodorants are presented for smelling or sniffing as individual odorants(e.g., a bottle containing eugenol (clove scent), another bottlecontaining isoamylacetate (banana scent), etc.). Pause et al. 2001observes that:

-   -   olfactory sensitivity, as measured by the threshold test, is        strongly reduced in patients with severe depression, and that        after successful treatment, this loss in sensitivity is reduced        and does not significantly differ from the control level, but        that    -   the subjective odor evaluations are not markedly changed in        general.

Pollatos et al. 2007 (Journal of Affective Disorders 102: 101-108)relates to olfactory perception in subjects with varying degrees ofdepressive symptoms (depressive symptoms ranging from score zero toscore nine according to the BECK DEPRESSION INVENTORY® scoring system).Olfactory perception included olfactory sensitivity and olfactorydiscrimination capacity. Olfactory sensitivity and olfactorydiscrimination capacity were measured using the odor threshold test andthe odor discrimination test, respectively, which are described inHummel et al. 1997 (Chem. Senses 22: 39-52). Said tests use pen-likeodor dispensing devices, i.e., sniffing sticks, containing and releasingpure odorants. The odor threshold test uses serial dilutions ofn-butanol to record the dilution at which the subject starts discerningthe odorant. The odor discrimination test is performed by presenting tothe subject three sniffing sticks each containing one odorant. Two ofthe three sticks contain the same odorant (e.g., isoamylacetate (bananascent)), while the third stick contains a different odorant (e.g.,anethol (aneth scent)). The task of the subject is to identify the stickthat has a different smell. Pollatos et al. 2007 observes that thedegree of depressive symptoms negatively correlates with the odordetection threshold value (olfactory sensitivity), while olfactorydiscrimination is not related to the degree of depressive symptoms.

The inventors demonstrate that, contrary to what could be expected orinferred from the prior art, olfactory discrimination is significantlyreduced in depressed subjects. The loss in olfactory discriminationcapacity is observed by submitting the depressed subject to mixturescontaining at least two different odorants.

SUMMARY OF THE INVENTION

The present application relates to the subject-matter as defined in theclaims as filed and as herein described.

The means of the application are notably useful in the field ofpsychiatric disorders involving mood disturbances, more particularlypsychiatric disorders involving mood depression, such as depressivedisorders, depressions, depressive disorders, major depressiveepisode(s) and Major Depressive Disorders (MDD).

The means of the application comprise at least one mixture of odorantsor at least one composition comprising odorants in mixture. Saidodorants consist of at least two different odorants, more particularlyof two different odorants.

The means of the application more particularly comprise the functionalassociation of at least two different mixtures or compositions of theapplication. The odorants are the same in each mixture or compositionthat belongs to the same functional association, but at least one ofsaid at least two mixtures or compositions contains said odorants in (a)proportion(s) that differ(s) from the other mixture(s) or composition(s)of the same functional association.

A reduction in the capacity to identify within at least one functionalassociation the at least one mixture or composition, which contains theodorants at different proportion(s) compared to the other mixture(s) orcomposition(s) of the said at least one functional association, isindicative of, or positively correlates with, a diagnosis of psychiatricdisorder involving mood disturbance, more particularly mood depression.More particularly, the reduction in said capacity is indicative of, orpositively correlates with the severity of the psychiatric diseaseand/or with non-response (or resistance) to antidepressant treatment.

The means of the application further comprise the collection of at leasttwo (different) functional associations of the application, as well askits comprising at least mixture or composition of the application, orat least two different mixtures or compositions of the application, orleast one functional association of the application, or at least twodifferent functional associations of the application.

The application also relates to the biotechnological or medicalapplications of the means of the application, notably in the field ofthe diagnosis and/or treatment of psychiatric disorders involving mooddisturbances, more particularly psychiatric disorders involving mooddepression.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: diagrammatic representation of an experimental design.

CORT=corticosterone; IHC=immunohistochemistry;

first bar (on the top)=vehicle;

penultimate bar (in the middle)=CORT;

last bar (at the bottom)=CORT, followed by CORT+fluoxetine (FLX or flx).

C57BL/6 male mice from Taconic Farms, Inc. (Tornbjergvej 40, DK-4623Lille Skensved, Denmark) were administered corticosterone (CORT, 5mg/kg/day in drinking water) for one month, to induce ananxiety/depression-like state. Depression-like behavior was checked bythe splash test, the open field test, elevated plus maze and noveltysuppressed feeding.

Then, 29 of these mice were put on a chronic fluoxetine regimen (FLX: 5mg/kg/day in drinking water, with CORT, 5 mg/kg/day, named CORT+FLXmice) [cf. last bar of the diagram], while 8 mice continued to receivecorticosterone chronically (named CORT mice) [cf. penultimate bar of thediagram]. Moreover, 8 control mice received the vehicle only (namedVEHICLE mice) [cf. first bar of the diagram].

FIG. 2: Mice are trained in olfactometers to discriminate between 2odorants: a positive stimulus (S+) and a negative stimulus (S−). Theolfactometer cage contains an odorant sampling port to inject odorantsinside the cage, and a water delivery tube to reward partiallywater-deprived animals (0) and (1). Cages are ventilated for fastodorant removal. When S+ odorant is injected through the sampling port,the mouse should go to the water delivery tube and hit it, resulting inwater reward (Correct answer: (2), left panel). If the mouse does nothit the water delivery tube it will not be rewarded (Error: miss). WhenS− odorant is injected into the cage, the mouse should not hit the waterdelivery tube (Correct answer: (2), right panel) since it will not berewarded (Error: false alarm).

TABLE 1 Correct Error Go out and lick No lick S+ Hit Reward Miss S−False alarm Correct rejection

FIGS. 3A, 3B and 3C: Effects of chronic anti-depressant treatment oncorticosterone-induced depression-like behavior in the splash test.

Results are expressed as the fraction of mice that did not groom within6 minutes [FIG. 3A], mean grooming duration [FIG. 3B] and mean groomingfrequency [FIG. 3C] following squirting of a 10% sucrose solution on theback coat of the mouse. Values plotted are mean±SEM (n=8/group in thevehicle and CORT group and n=28 in the CORT+flx group). CORT:corticosterone, flx: fluoxetine.

*: P<0.05 vs vehicle-treated, #: P<0.05 and ##: P<0.01 vs CORT-treated.

FIGS. 4A and 4B: Effects of chronic CORT and CORT+fluoxetineadministration on olfactory discrimination (FIG. 4A) and olfactorydetection (FIG. 4B). Results are expressed as the mean±SEM of correctresponse (a) or detection thresholds (−log₁₀ of odorant dilution). *:P<0.05, **: P<0.01.

FIGS. 5A and 5B: Scatter plot between depressive state (latency to groom[FIG. 5A] and number of grooming sessions [FIG. 5B] in the splash test)and olfactory detection.

FIG. 5A: r²=0.18; P=0.004; n=44;

FIG. 5B: r²=0.13; P=0.017; n=43.

FIGS. 6A and 6B: Graph depicting performance at the long-term olfactorymemory test (% correct response in the last block of training(acquisition: t0) and in the first block of testing (memory test: t30)(FIG. 6A)) and scatter plot between depressive state (grooming frequencyin the splash test) and long-term olfactory memory (FIG. 6B).

FIG. 6A: Results are expressed as the mean±SEM of correct response(n=8/group in the vehicle and CORT group and n=35 in the CORT+FLXgroup). ***P<0.001 between vehicle and CORT-treated, *P<0.05 betweenCORT and CORT+FLX

FIG. 6B: r²=0.11; **P=0.03; n=42

CORT: corticosterone, FLX: fluoxetine, t: time (day)

DETAILED DESCRIPTION OF THE INVENTION

The present application relates to the subject-matter as defined in theclaims as filed and as herein described.

The application demonstrates that, contrary to what could be expected orinferred from the prior art, olfactory discrimination is significantlyreduced in subjects affected by psychiatric disorders or diseasesinvolving mood disturbance, more particularly mood depression.

In the application, said psychiatric disorders or diseases notablyencompass depressive disorders and depression, more particularlydepressive episode(s), major depressive episode(s) and Major DepressiveDisorders (MDD).

In the application, the terms “psychiatric disorder”, “psychiatricdisease”, “mood disturbance”, “mood depression”, “depressive disorder”,“depression”, “major depressive episode” and “Major Depressive Disorder”have their respective ordinary meanings in the field.

Please see, for example, the Diagnostic and Statistical Manual of MentalDisorders (DSM), edited by the American Psychiatric Association (1000Wilson Boulevard, Suite 1825, Arlington, Va. 22209-3901, U.S.A.;http://www.psychiatry.org/home), e.g., the DMS-IV-TR edition (fourthedition, text revision, published in July 2000) or the DSM-V edition,which is to be published in 2013 [cf. http://psychiatryonline.org/].

Please see, for example, the BECK DEPRESSION INVENTORY® (BDI), moreparticularly the BDI-II edition published in 1996 (Beck, A. T., Steer,R. A., & Brown, G. K. 1996, Manual for the Beck Depression Inventory-II.San Antonio, Tex.: The Psychological Corporation, U.S.A.).

The application shows that said loss in olfactory discriminationcapacity is observed by submitting the subject to mixtures containing atleast two different odorants, more particularly to mixtures containingsaid at least two different odorants in different proportions.

More particularly, the application demonstrates that a subject affectedby a psychiatric disorder or disease involving mood disturbance, moreparticularly mood depression, has a lower capacity to discriminate amixture, which contains at least two different odorants in a certainproportion, from a mixture, which contains the same at least twodifferent odorants but in a different proportion. The applicationfurther demonstrates that said loss in olfactory discrimination capacityis not restored by standard SSRI/SNRI treatment, such as fluoxetinetreatment (PROZAC®). FIG. 4A illustrates this demonstration.

The application also provides a demonstration, which relates to theolfactory detection capacity, i.e., the threshold concentration at whicha subject stops or starts detecting one (mono-)odorant (the thresholdtest is performed by serial dilution of a single odorant, which is notmixed with any other odorant). The application demonstrates that theolfactory detection capacity is decreased in a subject affected by apsychiatric disorder or disease involving mood disturbance, moreparticularly mood depression, but is restored by standard SSRI/SNRItreatment, such as fluoxetine treatment (PROZAC®). FIG. 4B illustratesthis demonstration.

Hence, the application demonstrates that:

-   -   both the olfactory detection capacity and the olfactory        discrimination capacity are decreased in a subject affected by a        psychiatric disorder or disease involving mood disturbance, more        particularly mood depression, and that    -   standard SSRI/SNRI treatment, such as fluoxetine treatment        (PROZAC®), may restore the olfactory detection threshold, but        does not restore the olfactory discrimination capacity. The        terms “olfactory detection threshold”, “olfactory        discrimination” and “olfactory discrimination capacity” are        intended in accordance with their respective ordinary meanings        in the field. Please see e.g., Hummel et al. 1997 (Chem. Senses        22: 39-52).

As above mentioned (and below illustrated), the demonstration of theapplication notably stems from the fact that the inventors have overcomea prejudice in the art, more particularly concerning olfactorydiscrimination capacity (cf. background section), and from theconception and reduction to practice of an improved olfactorydiscrimination test, which involves mixtures comprising at least twodifferent odorants in different proportions. The means of theapplication have the further advantage of being non-invasive means.

The application therefore relates to a mixture of odorants and to acomposition comprising odorants in mixture. Said odorants consists of atleast two different odorants, more particularly of two differentodorants.

Said two, or at least two, odorants may be in, in mixture with, a(pharmaceutically-acceptable) vehicle, more particularly a vehicle,which is perceived to be odorless by mammals, or by at least one mammalrace or species, advantageously at least by humans (i.e., no odor and noscent perceived by olfactory cognition). Advantageously, said vehicledoes not alter the odor or scent emitted by each of said two, or of saidat least two, odorants. More particularly, said vehicle is structurallysuitable for homogeneously mixing said two, or said at least twoodorants, together, such as e.g., a solvent, a cream or a paste.Advantageously, said vehicle is a solvent. More particularly, saidvehicle is an odorless liquid solvent, such as water, mineral oil orpropylene glycol.

A mixture or composition of the application can be comprised on or in adevice or instrument for dispensing odor or scent, more particularly forolfactory testing. The application therefore relates to a device orinstrument for dispensing odor or scent, more particularly for olfactorytesting, which comprises a mixture or composition of the application.The device or instrument of the application comprises a structure fordispensing the odor(s), scent(s) or smell(s) emitted by the mixture orcomposition of the application, which is comprised in or on said deviceor instrument. More particularly, the structure of the device orinstrument of the application is adapted, or especially adapted, tosniffing or smelling by a mammal, more particularly to active sniffingor smelling by a mammal. More particularly, the structure of the deviceor instrument of the application is adapted, or especially adapted, toallow for a mammal to [actively] sniff or smell the odor(s), scent(s) orsmell(s) emitted by said mixture or composition.

In the application, the term “mammal” means any mammal, moreparticularly a non-human mammal, such as a rodent (more particularly amouse), or a human, still more particularly a diseased non-human mammalor a diseased human, even still more particularly a diseased non-humanmammal or a diseased human affected by or suspected of being affected bya psychiatric disorder or disease involving mood disturbance, moreparticularly mood depression.

According to a particular embodiment of the application, the term“mammal” means a human, more particularly a diseased human, still moreparticularly a diseased human affected by or suspected of being affectedby a psychiatric disorder or disease involving mood disturbance, moreparticularly mood depression.

More particularly, the olfactory device or instrument of the applicationis an odor dispensing device for assessing nasal chemosensoryperformance. It can function as a fully extra-nasal or extra-nostrildevice or instrument, or as a (partially) intra-nasal or intra-nostrildevice or instrument.

Devices or instruments for dispensing odor or scent, more particularlyfor olfactory testing are available to the person of ordinary skill inthe art. They include the olfactory devices or instruments that are usedin:

-   -   the “University of Pennsylvania Smell Identification Test”        (UPSIT) [Doty et al. 1984, Physiol. Behay. 32: 489-502; Doty et        al. 1984, Laryngoscope 94 (2Pt1): 176-178], commercialized e.g.,        by Sensonics, Inc. (P.O. Box 112 Haddon Heights, N.J. 08035,        USA) as the “Smell Identification TestT”,    -   its down-scaled version the “Cross Cultural Smell Identification        Test” (CC-SIT) [Doty et al. 1996, Laryngoscope 106 (3Pt1):        353-356],    -   the “Connecticut Chemosensory Clinical Research Center Test”        (CCCRC) [Cain et al. 1988, Laryngoscope 98:83-88; Cain 1989, Ear        Nose Throat J. 68: 316, 322-328], and    -   the olfactory test battery “SNIFFIN' STICKS™” [Kobal et al.        1996, Rhinology 34: 222-226; Hummel et al. 1997, Chem. Senses        22: 39-52; Kobal et al. 2000, Eur. Arch. Otorhinolaryngol. 257:        205-211; Hummel et al. 2001, Ann. Otol. Rhinol and Laryngol.        110: 976-981; Hummel et al. 2007, Eur. Arch. Otorhinolaryngol.        364(3): 237-243], commercialized e.g., by Burghardt Messtechnik        GmbH (Tinsdaler Weg 175, D-2280 Wedel, Germany; cf. commercial        references LA-13-00134, LA-13-00136, LA-13-00138, LA-13-00135        and LA-13-00137; http://www.burhart-mt.de).

The olfactory devices or instruments that are used in tests such as theUPSIT and the CC-SIT test comprise a plurality of cards or bookletpages, which each contain one odorant (or a control substance) embeddedtherein, e.g., by microencapsulation with a binder. The odorant isreleased by scratching a surface of the card or page.

The olfactory devices or instruments that are used in tests such as theCCCRC test comprise a plurality of bottles or jars, e.g., ofpolyethylene bottles, which each contain one odorant (or a controlsubstance), e.g., an odorant in liquid form. The bottle or jar isgenerally provided with a pop-up spout that fits to one or both nostrilsand dispenses the odorant to the sniffing user.

The olfactory devices or instruments that are used in tests such as theSNIFFIN' STICKS™ test comprise a plurality of capped felt-tip pens,which each contain one odorant (or a control substance) in a reservoiror absorbent material that is associated with the felt tip of the pen.The pen is de-capped to place the felt tip at a few centimeters from thenostrils (e.g., at about 2 cm), and to smell or sniff the odorantdispensed through the felt tip.

Therefore, examples of an olfactory device or instrument of theapplication comprise any structure, which can function as a reservoirfor odorants and as a dispenser of said odorants, such as:

-   -   an absorbent material, more particularly an absorbent fibrous        and/or cellulosic material, such as a filter, card or page,        optionally provided with microcapsules suitable for entrapping        the odorants,    -   a bottle or jar, e.g., a polyethylene bottle, optionally        provided with a pop-up spout that fits to one or both nostrils,    -   a pen-like dispensing device, such as a felt-tip pen of said        “SNIFFIN' STICKS™” battery.

Advantageously, the structure of the device is adapted to, or especiallyadapted to, the assessment of nasal chemosensory performance, moreparticularly the assessment of nasal chemosensory performance of ahuman.

An odorant is any substance or compound that emits an odor or scent, orany substance or compound that has a distinctive smell. An odor, scentor smell is the odor, scent or smell that is consciously perceived by amammal by smelling or sniffing though the nostril(s) (olfactorycognition).

Advantageously, an odorant is a substance or compound, which isidentifiable (by olfactory cognition) by said mammal, more particularlyby the human population to which the odorant is intended, moreparticularly by a human.

An odorant can be a substance or compound, which is volatile and/orhydrophobic, advantageously volatile and hydrophobic.

Advantageously, an odorant is a substance or compound, which isgenerally recognized as safe to mammals, more particularly to humans.

Advantageously, an odorant is a compound, more particularly amonomolecular compound.

According to an aspect of the application, each of said at least twoodorants, more particularly each of said two odorants, is amonomolecular compound, more particularly a monomolecular compound,which is identifiable by a human by olfaction cognition, still moreparticularly a monomolecular compound, which is volatile, hydrophobicand identifiable by a human by olfaction cognition, even still moreparticularly a monomolecular compound, which is volatile, hydrophobic,identifiable by a human by olfaction cognition and generally recognizedas safe to humans.

The expression “different odorants” means odorants, which emit differentodors or scents. Hence, an odorant is different from another odorant ifit emits an odor or scent that is different or perceived to be differentfrom said other odorant. More particularly, an odorant is different fromanother odorant if the majority of a representative number of normosmichealthy mammals belonging to the same mammal race or species perceivesthat they emit different odors or scents. For example, an odorant isdifferent from another odorant if more than 40% of a representativenumber of normosmic healthy mammals belonging to the same mammal race orspecies perceive that they emit different odors or scents. Moreparticularly, said percentage is more than 45%, more particularly morethan 50%, more particularly more than 55%, more particularly more than60%, more particularly more than 65%. A representative number ofnormosmic healthy mammals belonging to the same mammal race or speciescan be determined by the person of ordinary skill in the art dependingon the mammal race or species being tested. Such a number generally ismore than 10, more particularly more than 20.

According to an aspect of the application, each of said at least twoodorants, more particularly each of said two odorants, is amonomolecular compound emitting an odor or scent (as perceived by ahealthy normosmic human) selected from the group consisting of anise,apple, banana, caramel, chocolate, cinnamon, clove, cocoa, coconut,coffee, cola, dill, eucalyptus, fish, flower, honey, garlic, ginger,grapefruit, grass, lavender, leather, lemon, lilac, lily of the valley,licorice, melon, mint, mushroom, onion, orange, peach, pear, peppermint,pineapple, rose, spearmint, turpentine, raspberry, sesame oil, smokedmeat, soy sauce and vanilla.

According to an aspect of the application, each of said at least twoodorants, more particularly each of said two odorants is a monomolecularcompound emitting an odor or scent (as perceived by a healthy normosmichuman) selected from the group consisting of anise, banana, clove, dilland spearmint.

Examples of monomolecular compounds emitting such an odor or scentcomprise:

-   -   R-carvone (or L-carvone or carvone −), for spearmint odor or        scent,    -   S-carvone (or D-carvone or carvone +), for dill odor or scent,    -   isoamylacetate or n-butanol, more particularly isoamylacetate,        for banana odor or scent,    -   anethol, for anise odor or scent,    -   eugenol, for clove odor or scent,    -   2-phenylethanol for rose odor or scent,    -   geraniol for rose odor or scent,    -   linalool for lily of the valley odor or scent,    -   cineole for eucalyptus odor or scent,    -   D-limonene (or R-limonene or limonene +) for orange odor or        scent,    -   L-limonene (or S-limonene or limonene −) for turpentine odor or        scent,    -   menthol for mint odor or scent, and    -   cinnamon aldehyde for cinnamon odor or scent.

Please see e.g., the Arctander atlas (Arctander S. “Perfume and flavorchemicals: (aroma chemicals)”, Allured Publishing Corporation, CarolStream Ill., 1994).

Please also see the OdorDB database (Yale Center for MedicalInformatics, U.S.A.) available onhttp://senselab.med.yale.edu/odordb/eavObList.aspx?db=5&cl=1.

According to an aspect of the application, each of said at least twoodorants, more particularly each of said two odorants is a monomolecularcompound selected from the group consisting of R-carvone, S-carvone,isoamylacetate, anethol and eugenol.

As mentioned above, each of said at least two odorants, or each of saidtwo odorants, are different from each other. For example:

-   -   one of said at least two, or of said two, odorants is a        monomolecular compound emitting spearmint odor or scent (e.g.,        R-carvone), and the other of said at least two, or of said two,        odorants is:        -   a monomolecular compound emitting dill odor or scent (e.g.,            S-carvone) or        -   a monomolecular compound emitting banana odor or scent            (e.g., isoamylacetate) or        -   a monomolecular compound emitting anise odor or scent (e.g.,            anethol) or        -   a monomolecular compound emitting clove odor or scent (e.g.,            eugenol),            or    -   one of said at least two, or of said two, odorants is a        monomolecular compound emitting dill odor or scent (e.g.,        S-carvone), and the other of said at least two, or of said two,        odorants is        -   a monomolecular compound emitting spearmint odor or scent            (e.g., R-carvone) or        -   a monomolecular compound emitting banana odor or scent            (e.g., isoamylacetate) or        -   a monomolecular compound emitting anise odor or scent (e.g.,            anethol) or        -   a monomolecular compound emitting clove odor or scent (e.g.,            eugenol),            or    -   one of said at least two, or of said two, odorants is a        monomolecular compound emitting banana odor or scent (e.g.,        isoamylacetate), and the other of said at least two, or of said        two, odorants is        -   a monomolecular compound emitting dill odor or scent (e.g.,            S-carvone) or        -   a monomolecular compound emitting spearmint odor or scent            (e.g., R-carvone) or        -   a monomolecular compound emitting anise odor or scent (e.g.,            anethol) or        -   a monomolecular compound emitting clove odor or scent (e.g.,            eugenol),            or    -   one of said at least two, or of said two, odorants is a        monomolecular compound emitting anise odor or scent (e.g.,        anethol), and the other of said at least two, or of said two,        odorants is        -   a monomolecular compound emitting dill odor or scent (e.g.,            S-carvone) or        -   a monomolecular compound emitting banana odor or scent            (e.g., isoamylacetate) or        -   a monomolecular compound emitting spearmint odor or scent            (e.g., R-carvone) or        -   a monomolecular compound emitting clove odor or scent (e.g.,            eugenol),            or    -   one of said at least two, or of said two, odorants is a        monomolecular compound emitting clove odor or scent (e.g.,        eugenol), and the other of said at least two, or of said two,        odorants is        -   a monomolecular compound emitting dill odor or scent (e.g.,            S-carvone) or        -   a monomolecular compound emitting banana odor or scent            (e.g., isoamylacetate) or        -   a monomolecular compound emitting anise odor or scent (e.g.,            anethol) or        -   a monomolecular compound emitting spearmint odor or scent            (e.g., R-carvone).

In a mixture or composition of the application, said at least twoodorants, or said two odorants, are contained in mixture and in anyproportion that the person of ordinary skill in the art findsappropriate.

For example, said at least two odorants, or said two odorants, arecontained in the mixture or composition of the application in aproportion ranging from 1:1 to 1:5, more particularly in a proportionranging from 1:1.5 to 1:4, for example in a proportion of 1:1.5, 1:2,1:2.5, 1:3, 1:3.5 or 1:4. A “X:Y” proportion means X part(s) of one ofsaid at least two, or of said two, odorants for Y part(s) of the otherof said at least two, or of said two, odorants (X and Y can identical ordifferent). Said part values are volume parts or weight parts, moreparticularly volume parts.

For example, said at least two odorants, or said two odorants, arecontained in the mixture or composition of the application in aproportion ranging from 0.8%/0.2% to 0.2%/0.8% to 0.2%/0.8%, moreparticularly in a proportion ranging from 0.6%/0.4% to 0.4%/0.6%, forexample in a proportion of 0.8%/0.2%, 0.6%/0.4%, 0.4%/0.6% or 0.2%/0.8%.A proportion of “X %/Y %” means X % of one of said at least two, or ofsaid two, odorants and Y % of the other of said at least two, or of saidtwo, odorants. A % value of an odorant is the volume or weight, moreparticularly the volume, of said odorant expressed with respect to thetotal volume or weight of the mixture in said mixture, more particularlyto the total volume of said mixture.

For example, said at least two odorants, or said two odorants, arecontained in the mixture or composition of the application in aproportion ranging from 8/2 to 2/8, more particularly in a proportionranging from 6/4 to 4/6, for example in a proportion of 8/2, 6/4, 4/6 or2/8. A proportion of “X/Y” means a concentration of X of one of said atleast two, or of said two, odorants and a concentration of Y of theother of said at least two, or of said two, odorants. The concentrationsX and Y are expressed in the same unit, for example in volume/volumepercent, in volume/weight percent or in weight/weight percent, moreparticularly in volume/volume percent, and are expressed with respect tothe total volume or weight of the mixture in said mixture, moreparticularly to the total volume of said mixture.

More particularly, the application relates to the functional associationof several (different) mixtures or compositions of the application forsequential use. Each of said several mixtures can be (separately)comprised in or on a device or instrument for dispensing odor or scentas above-described (and as below-illustrated).

In a functional association of the application, said several (different)mixtures or compositions are (and remain) distinct or separate from eachother. Hence, when they are contained in or on a device or instrumentfor dispensing odor or scent, they are not mixed together.Advantageously, they are not contained in the same device or instrument.For example, each of said several mixtures or compositions is separatelycontained in an odor dispensing device for assessing nasal chemosensoryperformance as above-described (and as below-illustrated).

The odorants are the same in each mixture or composition that belongs tothe same functional association, i.e., they are the same substances orcompounds.

At least one of said several mixtures or compositions contains saidodorants in a proportion that differs from the other mixture(s) orcomposition(s) of the same functional association.

Hence, the proportion of one of said (at least) two odorants withrespect to the other of said (at least) two odorants in a firstcomposition of an association is different from their proportion in atleast one second composition of the same functional association.

Therefore, the application relates to a functional association, whichcomprises:

-   -   at least one first mixture or composition comprising odorants,        wherein the odorants of said at least one first mixture or        composition consist of (at least) two different odorants, and,        separately or distinctly from said at least one first mixture or        composition,    -   at least one second mixture or composition comprising odorants,        wherein the odorants of said at least one second mixture or        composition consist of (at least) two different odorants,        wherein the odorants of said at least one first mixture or        composition are the same compounds as the odorants of said at        least one second mixture or composition, and        wherein the proportion of said odorants (with respect to each        other) in said at least one first mixture or composition is        different from their proportion in said at least one second        mixture or composition.

For example, the concentration of at least one odorant in said at leastone first mixture or composition is different from its proportion insaid at least one second mixture or composition.

For example, the respective concentrations of the (at least two)odorants in said at least one first mixture or composition are differentfrom their respective concentrations in said at least one second mixtureor composition.

According to an advantageous aspect of the application, said at leastone first composition and said at least one second composition are forsequential use, more particularly for sequential use in the detection ofolfactory discrimination impairment in a human, more particularly in adiseased human.

A functional association of the application may comprise any number ofmixtures or compositions of the application that the person of ordinaryskill in the art may find appropriate. For example, a functionalassociation of the application may comprise two or three mixtures orcompositions of the application.

For example, a functional association of the application comprises twoor three mixtures or compositions of the application, which are distinctor separate from each other, wherein the odorants of said two or threemixtures or compositions are the same but are contained in one of saidtwo or three mixtures or compositions in a proportion that differs fromthe remaining one or two mixtures or compositions. In the case of anumber of three mixtures or compositions of the application, saidremaining two mixtures or compositions can be identical, i.e.,duplicate.

The application thus relates to a functional association, whichcomprises:

-   -   a first composition comprising odorants, wherein the odorants of        said first composition consist of at least two different        odorants, and, separately or distinctly from said first        composition,    -   a second composition comprising odorants, wherein the odorants        of said second composition consist of at least two different        odorants, wherein said second composition is contained in        duplicate.

The application thus relates to a functional association, whichcomprises:

-   -   a first composition comprising odorants, wherein the odorants of        said first composition consist of at least two different        odorants, and, separately or distinctly from said first        composition,    -   a second composition comprising odorants, wherein the odorants        of said second composition consist of at least two different        odorants, and, separately or distinctly from said first        composition and from said second composition,    -   a third composition comprising odorants, wherein the odorants of        said third composition consist of at least two different        odorants, and wherein said third composition is a duplicate of        said second composition.

Since said third composition is a duplicate of said second composition,the odorants of said second composition are the same compounds as theodorants of said third composition, and the proportion of the odorantswith respect to each other in said second composition is identical totheir proportion in said third composition.

Since said first composition belongs to the same functional associationas said second and third compositions, the odorants of said firstcomposition are the same compounds as the odorants of said secondcomposition and as the odorants of said third composition, but theproportion of the odorants with respect to each other in said firstcomposition is different from their proportion in said secondcomposition and in said third composition.

Advantageously, the difference in proportions within the same functionalassociation is sufficient to be distinguishable by a healthy normosmichuman. Hence, according to an advantageous aspect of the application,the at least one mixture or composition, which contains said odorants ina proportion that differs from the other mixture(s) or composition(s) ofthe same association, is consciously perceived (olfactory cognition) asemitting an odor or scent that is different from the odor or scentemitted by the other mixture(s) or composition(s) of the association.

For example, a functional association of the application comprises (atleast) two mixtures or compositions of the application, which aredistinct or separate from each other, wherein the odorants of each ofsaid (at least) two mixtures or compositions are the same two or thesame at least two odorants, and wherein one of said two, or of said atleast two, odorants is contained in one of said (at least) two mixturesor compositions in a 8/2 proportion, whereas the other of said two, orof said at least two, odorants is contained in the other of said (atleast) two mixtures or compositions in a 2/8 proportion.

For example, a functional association of the application comprises threemixtures or compositions of the application, which are separate fromeach other (two of said three mixtures compositions being duplicatecompositions as described above), wherein the odorants of each of saidthree mixtures or compositions are the same two or the same at least twoodorants, and wherein one of said two, or of said at least two, odorantsis contained in one of said three mixtures or compositions in a 8/2proportion, whereas the other of said two, or of said at least two,odorants is contained in each of the two other (duplicate) mixtures orcompositions in a 2/8 proportion.

For example, a functional association of the application comprises (atleast) two mixtures or compositions of the application, which aredistinct or separate from each other, wherein the odorants of each ofsaid (at least) two mixtures or compositions are the same two or thesame at least two odorants, and wherein one of said two, or of said atleast two, odorants is contained in one of said (at least) two mixturesor compositions in a 6/4 proportion, whereas the other of said two, orof said at least two, odorants is contained in the other of said (atleast) two mixtures or compositions in a 4/6 proportion.

For example, a functional association of the application comprises threemixtures or compositions of the application, which are separate fromeach other (two of said three mixtures compositions being duplicatecompositions as described above), wherein the odorants of each of saidthree mixtures or compositions are the same two or the same at least twoodorants, and wherein one of said two, or of said at least two, odorantsis contained in one of said three mixtures or compositions in a 6/4proportion, whereas the other of said two, or of said at least two,odorants is contained in each of the two other (duplicate) mixtures orcompositions in a 4/6 proportion.

For example, a functional association of the application comprises (atleast) two mixtures or compositions of the application, which aredistinct or separate from each other, wherein the odorants of each ofsaid (at least) two mixtures or compositions are R-carvone and S-carvonein mixture, and wherein one of said (at least) two mixtures orcompositions contains R-carvone and S-carvone in a 8/2 proportion,whereas the other of said (at least) two mixtures or compositionscontains R-carvone and S-carvone in a 2/8 proportion.

For example, a functional association of the application comprises threemixtures or compositions of the application, which are separate fromeach other (two of said three mixtures compositions being duplicatecompositions as described above), wherein the odorants of each of saidthree mixtures or compositions are R-carvone and S-carvone in mixture,and wherein one of said three mixtures or compositions containsR-carvone and S-carvone in a 8/2 proportion, whereas each of the twoother (duplicate) mixtures or compositions contains R-carvone andS-carvone in a 2/8 proportion.

For example, a functional association of the application comprises (atleast) two mixtures or compositions of the application, which aredistinct or separate from each other, wherein the odorants of each ofsaid (at least) two mixtures or compositions are isoamylacetate andanethol in mixture, and wherein one of said (at least) two mixtures orcompositions contains isoamylacetate and anethol in a 8/2 proportion,whereas the other of said (at least) two mixtures or compositionscontains isoamylacetate and anethol in a 2/8 proportion.

For example, a functional association of the application comprises threemixtures or compositions of the application, which are separate fromeach other (two of said three mixtures compositions being duplicatecompositions as described above), wherein the odorants of each of saidthree mixtures or compositions are isoamylacetate and anethol inmixture, and wherein one of said three mixtures or compositions containsisoamylacetate and anethol in a 8/2 proportion, whereas each of the twoother (duplicate) mixtures or compositions contains isoamylacetate andanethol in a 2/8 proportion.

For example, a functional association of the application comprises (atleast) two mixtures or compositions of the application, which aredistinct or separate from each other, wherein the odorants of each ofsaid (at least) two mixtures or compositions are anethol and eugenol inmixture, and wherein one of said two (at least) mixtures or compositionscontains anethol and eugenol in a 8/2 proportion, whereas the other ofsaid (at least) two mixtures or compositions contains anethol andeugenol in a 2/8 proportion.

For example, a functional association of the application comprises threemixtures or compositions of the application, which are distinct orseparate from each other (two of said three mixtures compositions beingduplicate compositions as described above), wherein the odorants of eachof said three mixtures or compositions are anethol and eugenol inmixture, and wherein one of said three mixtures or compositions containsanethol and eugenol in a 8/2 proportion, whereas each of the two other(duplicate) mixtures or compositions contains anethol and eugenol in a2/8 proportion.

The application also relates to a kit comprising at least one functionalassociation of the application.

The application further relates to the collection of at least two(different) functional associations of the application for sequentialuse, more particularly to a kit comprising at least two functionalassociations of the application.

Said at least two (different) functional associations of the applicationare (and remain) distinct or separate from each other. The odorants ofeach of said at least two (different) functional associations can be thesame compounds or different compounds. The proportions at which they arecontained in each of said at least two (different) functionalassociations can be the same proportions or different proportions.

Hence, the application relates to the collection of:

-   -   at least one first mixture or composition comprising odorants,        wherein the odorants of said at least one first mixture or        composition consist of (at least) two different odorants,    -   at least one second mixture or composition comprising odorants,        wherein the odorants of said at least one second mixture or        composition consist of (at least) two different odorants,    -   at least one third mixture or composition comprising odorants,        wherein the odorants of said at least one third mixture or        composition consist of two different odorants,    -   at least one fourth mixture or composition comprising odorants,        wherein the odorants of said at least one fourth mixture or        composition consist of two different odorants, wherein said at        least one first, second, third and fourth mixtures or        compositions are separate or distinct from each other,        wherein the odorants of said at least one first mixture or        composition are the same compounds as the odorants of said at        least one second mixture or composition, and        wherein the proportion of the odorants (with respect to each        other) in said at least one first mixture or composition is        different from their proportion in said at least one second        mixture or composition,        wherein the odorants of said at least one third mixture or        composition are the same compounds as the odorants of said at        least one fourth mixture or composition, and        wherein the proportion of the odorants (with respect to each        other) in said at least one third mixture or composition is        different from their proportion in said at least one fourth        mixture or composition.

The (at least two) odorants of said at least one first and secondmixtures or compositions can be different from the (at least) twoodorants of said at least one third and fourth mixtures or compositions.

The (at least two) odorants of said at least one first and secondmixtures or compositions can be the same compounds as the (at least) twoodorants of said at least one third and fourth mixtures or compositions,but in different proportions.

Said (at least one) second mixture or composition can be contained induplicate, as described above. Said (at least one) fourth mixture orcomposition can be contained in duplicate, as described above.

For example, a kit of the application comprises at least one (first)functional association of the application, wherein the odorants are in8/2 and 2/8 proportions, and at least one other (second) functionalassociation, which comprises the same odorants as said first functionalassociation but in different proportions, e.g., in 6/4 and 4/6proportions. In each of said first and second associations, one of the(at least) two mixtures or compositions can be contained in duplicate(as above described).

For example, a kit of the application comprises at least one (first)functional association of the application, wherein the odorants are in8/2 and 2/8 proportions, and at least one other (second) functionalassociation, which comprises different odorants as said first functionalassociation at the same or in different proportions, e.g., in 8/2 and2/8 proportions or in 6/4 and 4/6 proportions. In each of said first andsecond associations, one of the (at least) two mixtures or compositionscan be contained in duplicate (as above described).

For example, a kit of the application comprises

-   -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are R-carvone and S-carvone in mixture, and wherein one of said        (at least) two mixtures or compositions contain R-carvone and        S-carvone in a 8/2 proportion, whereas the other of said (at        least) two mixtures or compositions contain R-carvone and        S-carvone in a 2/8 proportion (one of said (at least) two        mixtures or compositions can be contained in duplicate, as        above-described); and    -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are R-carvone and S-carvone in mixture, and wherein one of said        (at least) two mixtures or compositions contain R-carvone and        S-carvone in a 6/4 proportion, whereas the other of said (at        least) two mixtures or compositions contain R-carvone and        S-carvone in a 6/4 proportion (one of said (at least) two        mixtures or compositions can be contained in duplicate, as        above-described).

For example, a kit of the application comprises:

-   -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are R-carvone and S-carvone in mixture, and wherein one of said        (at least) two mixtures or compositions contain R-carvone and        S-carvone (e.g., in a 8/2 or 6/4 proportion), whereas the other        of said (at least) two mixtures or compositions contain        R-carvone and S-carvone (e.g., in a 2/8 or 6/4 proportion,        respectively) (one of said (at least) two mixtures or        compositions can be contained in duplicate, as above-described);        and    -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are isoamylacetate and anethol in mixture, and wherein one of        said (at least) two mixtures or compositions contain        isoamylacetate and anethol (e.g., in a 8/2 or 6/4 proportion),        whereas the other of said (at least) two mixtures or        compositions contain isoamylacetate and anethol (e.g., in a 2/8        or 6/4 proportion, respectively) (one of said (at least) two        mixtures or compositions can be contained in duplicate, as        above-described).

For example, a kit of the application comprises:

-   -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are R-carvone and S-carvone in mixture, and wherein one of said        (at least) two mixtures or compositions contain R-carvone and        S-carvone (e.g., in a 8/2 or 6/4 proportion), whereas the other        of said (at least) two mixtures or compositions contain        R-carvone and S-carvone (e.g., in a 2/8 or 6/4 proportion,        respectively) (one of said (at least) two mixtures or        compositions can be contained in duplicate, as above-described);        and    -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are anethol and eugenol in mixture, and wherein one of said (at        least) two mixtures or compositions contain anethol and eugenol        (e.g., in a 8/2 or 6/4 proportion), whereas the other of said        (at least) two mixtures or compositions contain anethol and        eugenol (e.g., in a 2/8 or 6/4 proportion, respectively) (one of        said (at least) two mixtures or compositions can be contained in        duplicate, as above-described).

For example, a kit of the application comprises:

-   -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are isoamylacetate and anethol in mixture, and wherein one of        said (at least) two mixtures or compositions contain        isoamylacetate and anethol (e.g., in a 8/2 or 6/4 proportion),        whereas the other of said (at least) two mixtures or        compositions contain isoamylacetate and anethol (e.g., in a 2/8        or 6/4 proportion, respectively) (one of said (at least) two        mixtures or compositions can be contained in duplicate, as        above-described); and    -   (at least) two mixtures or compositions of the application,        which are distinct or separate from each other, wherein the        odorants of each of said (at least) two mixtures or compositions        are anethol and eugenol in mixture, and wherein one of said (at        least) two mixtures or compositions contain anethol and eugenol        (e.g., in a 8/2 or 6/4 proportion), whereas the other of said        (at least) two mixtures or compositions contain anethol and        eugenol (e.g., in a 2/8 or 6/4 proportion, respectively) (one of        said (at least) two mixtures or compositions can be contained in        duplicate, as above-described).

A mixture or composition of the application, more specifically afunctional association or a kit of the application, or a collection offunctional associations or a kit of the application, enables measuringthe olfactory capacity of a mammal, more particularly the olfactorydiscrimination capacity of a mammal, more particularly detecting and/ormeasuring olfactory discrimination impairment in a mammal. Moreparticularly, said mammal is a diseased mammal. More particularly, saidmammal is a human, notably a diseased human, more particularly adiseased human affected by or suspected of being affected by apsychiatric disorder or disease involving mood disturbance, moreparticularly mood depression.

The several mixtures or compositions of a functional association of theapplication can be sequentially placed in smelling or sniffing contactwith said mammal. The experimenter, laboratory technician or physicianrecords whether said mammal succeeds in identifying, within the mixturesor compositions of the same association, the at least one mixture orcomposition that contains the (two, or at least two) odorants in aproportion that differs from the other mixture(s) or composition(s).

The person of ordinary skill in the art may appreciate that saidsequential smelling or sniffing is advantageously performed underconditions that prevent or avoid olfaction contamination. For example,said sequential smelling or sniffing is advantageously performed in aroom where aeration is sufficient to prevent or avoid olfactioncontamination, and according to a time sequence, which prevents oravoids olfaction contamination from one mixture or composition to thenext mixture or composition.

The person of ordinary skill in the art may appreciate that saidsequential smelling or sniffing can be performed under blind testing.

If desired or required, said smelling or sniffing can be repeated withthe same and/or with another functional association of the application.

A mixture or composition of the application, more specifically afunctional association or a kit of the application, or a collection offunctional associations or a kit of the application, can be furtherfunctionally associated with, or a kit of the application can furthercomprise any other additional element, such as at least one additionalmeans, device, instrument, composition, substance or compound, that theperson of ordinary skill in the art finds appropriate to measureolfactory capacity, more particularly to detect and/or measure olfactoryimpairment.

For example, said additional element can be means for measuring theolfactory detection threshold of a mammal or human, more particularly adiseased mammal or human.

Means for measuring olfactory detection threshold can for examplecomprise a plurality of compositions, wherein each composition of saidplurality contains only one odorant, and wherein all the compositions ofsaid plurality contains the same one odorant and form a serial dilutionof said same one odorant.

Said odorant can be as defined above. For example, said odorant can ben-butanol or 2-phenylethanol. Please see Hummel et al. 1997, Chem.Senses 22: 39-52.

The application relates to the medical or biotechnological applicationsof at least one product of the application, i.e., at least one mixtureor composition of the application, more specifically of at least onefunctional association, collection or kit of the application. Saidapplications comprise particularly methods and uses.

More particularly, a method or use of the application comprises thesmelling or sniffing of at least one mixture or composition of theapplication, more particularly the sequential smelling or sniffing of atleast two different mixtures or compositions of the application, moreparticularly the sequential smelling or sniffing of at least twodifferent mixtures or compositions that belong to the same functionalassociation as above-described (and below illustrated), moreparticularly of mixtures or compositions that belong to at least twodifferent functional associations as above-described (and below)illustrated.

More particularly, said smelling or sniffing can be active smelling orsniffing.

A method or use of the application may notably comprise:

-   -   allowing at least one nostril of a subject to be in smelling or        sniffing contact with at least one functional association of the        application, and    -   determining and/or measuring the capacity of said subject to        identify within said at least one functional association the at        least one mixture or composition, which contains the odorants at        different proportion(s) compared to the other mixture(s) or        composition(s) of the said at least one functional association.

As above mentioned (and below illustrated), said smelling or sniffing,more particularly said sequential smelling or sniffing, allows fordetermining and/or measuring the olfactory capacity, more particularlythe olfactory discrimination capacity, of the smelling or sniffingsubject.

More particularly, a subject affected by a psychiatric disorder ordisease involving mood disturbance, more particularly mood depression,has a lower capacity to discriminate a mixture, which contains at leasttwo different odorants in a certain proportion, from a mixture, whichcontains the same at least two different odorants but in a differentproportion, i.e., has a lower capacity to discriminate between twomixtures or compositions that belong to the same functional associationof the application.

The lower the capacity of the subject the higher the severity of thepsychiatric disease.

As mentioned above (and as apparent from the examples below), thecapacity of discriminating between mixtures of the same functionalassociation is indicative of, or positively correlates with, theolfactory capacity, more particularly the olfactory discriminationcapacity of said subject.

For example:

-   -   a subject (subject no 1) discriminates between the (at least)        two mixtures or compositions of a first functional association,        which comprise said odorants at certain proportions (e.g., at        8/2 and 2/8 proportions, respectively) [discrimination test no        1], but does not discriminate between the (at least) two        mixtures or compositions of a second functional association,        which comprise said odorants at proportions, which are closer to        each other (e.g., at 6/4 and 4/6 proportions) [discrimination        test no 1],        whereas    -   the same subject (subject no 1) did not succeed in any of the        two discrimination tests [discrimination tests no 1 and no 2]        before he/she received antidepressant treatment.

In this example, it can be concluded that subject no 1 is responsive tothe antidepressant treatment.

Another example is the following example:

-   -   a subject (subject no 1) discriminates between the (at least)        two mixtures or compositions of a first functional association,        which comprise said odorants at certain proportions (e.g., at        8/2 and 2/8 proportions, respectively) [discrimination test no        1], but does not discriminate between the (at least) two        mixtures or compositions of a second functional association,        which comprise said odorants at proportions, which are closer to        each other (e.g., at 6/4 and 4/6 proportions) [discrimination        test no 1],        whereas    -   another subject (subject no 2) does not succeed in any of the        two discrimination tests [discrimination tests no 1 and no 2].

In this example, it can be concluded that the severity of thepsychiatric disease of subject no 2 is higher than the severity of thepsychiatric disease of subject no 1.

A method or use of the application is advantageously performed in asubject in need thereof.

Said subject is a mammal as above described, more particularly a human,still more particularly a diseased human, still more particularly adiseased human affected by or suspected of being affected by apsychiatric disorder or disease involving mood disturbance, moreparticularly mood depression.

According to an aspect of the application, said subject is at a stagewhere he/she does not show the symptoms of a severe stage of psychiatricdisorder or disease involving mood disturbance, more particularly mooddepression.

Advantageously, said subject does not show or does not have severedepression. More particularly, the subject may show minimal, mild ormoderate depression, more particularly minimal or mild depression.

For example, according to the BDI-II test, said subject may score lessthan 29 (moderate, mild or minimal depression), more particularly lessthan 20 (mild or minimal depression), still more particularly less than14 (minimal depression).

Said applications notably comprise the use of said at least one productof the application in the diagnosis, more particularly in the in vivodiagnosis of a psychiatric disorder or disease involving mooddisturbance, more particularly mood depression.

According to an aspect of the application, said use in the (in vivo)diagnosis of a psychiatric disorder or disease involving mooddisturbance, more particularly mood depression, further comprisesdetermining whether said subject has a reduced olfactory capacity, moreparticularly a reduced olfactory discrimination capacity, compared to ahealthy and normosmic control subject. A reduced olfactory capacity,more particularly a reduced olfactory discrimination capacity, isindicative of a psychiatric disorder or disease involving mooddisturbance, more particularly mood depression. The extent of reductionof olfactory capacity, more particularly of olfactory discriminationcapacity, is indicative of, or positively correlates with, the severityof mood disturbance, more particularly of mood depression, in saidsubject.

Said applications notably comprise the use of said at least one productof the application to determine or measure the severity of a psychiatricdisorder or disease that involves mood disturbance, more particularlydepression. Said applications more particularly comprise the use of saidat least one product of the application in the diagnosis, moreparticularly the in vivo diagnosis of the severity of a psychiatricdisorder or disease that involves mood disturbance, more particularlymood depression.

According to an aspect of the application, said use in determiningand/or measuring the severity of a psychiatric disorder or disease thatinvolves mood disturbance, more particularly mood depression, and/orsaid use in the (in vivo) diagnosis of the severity of a psychiatricdisorder or disease that involves mood disturbance, more particularlymood depression, further comprise(s) determining and/or measuring theextent of reduction in olfactory discrimination capacity of saidsubject. The higher said extent the higher said severity.

Said applications notably comprise the use of said at least one productof the application in the treatment of a psychiatric disorder or diseaseinvolving mood disturbance, more particularly mood depression.

According to an aspect of the application, said use in the treatment ofa psychiatric disorder or disease involving mood disturbance, moreparticularly mood depression, further comprises selecting a treatment,more particular an antidepressant treatment, which increases theolfactory capacity, more particularly the olfactory discriminationcapacity, of said subject, and administering said selected treatment (orantidepressant treatment) to said subject.

According to an alternative or complementary aspect of the application,said use in the treatment of a psychiatric disorder or disease involvingmood disturbance, more particularly mood depression, further comprisesmodifying and/or adjusting the nature and/or dosage of the treatmentgiven or applied to the patient so as to increase the olfactorycapacity, more particularly the olfactory discrimination capacity, ofsaid subject. Said applications notably comprise the use of said atleast one product of the application in determining and/or measuringand/or monitoring the efficiency of a treatment that is intended fortreating a psychiatric disorder or disease involving mood disturbance,more particularly depression. More particularly, said applicationsnotably comprise the use of said at least one product of the applicationin the diagnosis, more particularly the in vivo diagnosis, of responseor non-response (or resistance) to a treatment that is intended fortreating a psychiatric disorder or disease involving mood disturbance,more particularly mood depression.

According to an aspect of the application, said use in the (in vivo)diagnosis of response or non-response (or resistance) to a treatmentthat is intended for treating a psychiatric disorder or diseaseinvolving mood disturbance, more particularly mood depression, furthercomprises submitting a subject, who has received said treatment, to saidsequential smelling or sniffing, and determining whether said treatmentincreases or decreases the olfactory discrimination capacity of saidsubject. An increased olfactory discrimination capacity is indicative ofresponse to said treatment. A reduced or unmodified (e.g.,non-significantly different) olfactory discrimination capacity isindicative of non-response (or resistance) to said treatment.

According to an aspect of the application, said use in the (in vivo)diagnosis of response or non-response (or resistance) to a treatmentthat is intended for treating a psychiatric disorder or diseaseinvolving mood disturbance, more particularly mood depression, furthercomprises:

-   -   administering a candidate antidepressant treatment to said        subject,    -   placing said subject in smelling or sniffing contact with said        at least one product of the application,    -   determining whether said candidate antidepressant treatment        increases the olfactory capacity, more particularly the        olfactory discrimination capacity, of said subject.

Said subject can be diagnosed to be non-responsive (or resistant) tosaid candidate antidepressant treatment if said olfactory capacity, moreparticularly said olfactory discrimination capacity, is not increased.Said subject can be diagnosed to be responsive to said candidateantidepressant treatment if said olfactory capacity, more particularlysaid olfactory discrimination capacity, is increased.

Said treatment can e.g., be a pharmaco-therapeutic treatment, e.g., atreatment comprising the administration of at least one SelectiveSerotonin Reuptake Inhibitor (SSRI) and/or at least one Serotonin andNoradrenalin Reuptake Inhibitor (SNRI), for example the administrationof PROZAC®.

Alternatively or complementarily, said treatment can be a treatmentcomprising the administration of electroshock(s), e.g.,electroconvulsivotherapy

Said applications notably comprise the use of said at least one productof the application to measure the olfactory capacity, more particularlythe olfactory discrimination capacity of a subject.

Said applications notably comprise the use of said at least one productof the application to identify a treatment suitable for (or useful in)treating a psychiatric disorder or disease that involves mooddisturbance, more particularly mood depression. Said use may comprise:

-   -   using at least one product of the application to measure the        olfactory discrimination capacity of a subject affected by a        psychiatric disorder or disease that involves mood disturbance,        more particularly mood depression,    -   submitting said subject to a candidate antidepressant treatment,    -   determining whether said candidate treatment lessen the severity        of said psychiatric disorder or disease in said subject,        whereby said candidate antidepressant treatment is identified as        suitable for (or useful in) treating a psychiatric disorder or        disease that involves mood disturbance, more particularly mood        depression.

In the implementation of this use, said subject may advantageously be anon-human mammal, more particularly a rodent, such as a mouse.

The application also relates to a method of manufacturing a deviceuseful in or for the diagnosis or the treatment of a psychiatricdisorder or disease that involves mood disturbance, more particularlydepression, which comprises:

-   -   producing at least one mixture or composition of the        application, or at least two different mixture(s) or        composition(s) of the application, or at least one functional        association of the application, or at least one kit comprising        at least one functional association of the application, or at        least one collection of at least two functional associations of        the application, or at least one kit comprising at least one        collection of the application,    -   placing said at least one mixture or composition in or on a        device, which comprises a structure for dispensing the odor or        scent emitted by said mixture(s) or composition(s), and which is        adapted to sniffing or smelling the emitted odor or scent by a        mammal, more particularly in or on an odor dispensing device for        assessing nasal chemosensory performance.

The application also relates to the device obtainable by, or obtained bysaid method of manufacture.

In the application, unless specified otherwise or unless a contextdictates otherwise, all the terms have their ordinary meaning in therelevant field(s).

The term “comprising”, which is synonymous with “including” or“containing”, is open-ended, and does not exclude additional, unrecitedelement(s), ingredient(s) or method step(s), whereas the term“consisting of” is a closed term, which excludes any additional element,step, or ingredient which is not explicitly recited.

The term “essentially consisting of” is a partially open term, whichdoes not exclude additional, unrecited element(s), step(s), oringredient(s), as long as these additional element(s), step(s) oringredient(s) do not materially affect the basic and novel properties ofthe invention.

The term “comprising” (or “comprise(s)”) hence includes the term“consisting of” (“consist(s) of”), as well as the term “essentiallyconsisting of” (“essentially consist(s) of”). Accordingly, the term“comprising” (or “comprise(s)”) is, in the present application, meant asmore particularly encompassing the term “consisting of” (“consist(s)of”), and the term “essentially consisting of” (“essentially consist(s)of”).

In an attempt to help the reader of the present application, thedescription has been separated in various paragraphs or sections. Theseseparations should not be considered as disconnecting the substance of aparagraph or section from the substance of another paragraph or section.To the contrary, the present description encompasses all thecombinations of the various sections, paragraphs and sentences that canbe contemplated. Each of the relevant disclosures of all referencescited herein is specifically incorporated by reference. The followingexamples are offered by way of illustration, and not by way oflimitation.

EXAMPLES Example 1 Olfactory Test on a Non-Human Mammal Model

We investigated olfaction in an animal model of depression: the CORTmodel (David et al. 2009, Neuron 62(4): 479-493, including SupplementalData). This model is based on the disruption of the equilibrium of thehypothalamo-pituitary-adrenal (HPA) axis, reminiscent of what can beobserved in human subjects diagnosed with Major Depressive Disorder(MDD). The model involves chronic administration of a low dose ofcorticosterone in mice, inducing a high anxiety- and depressive-likebehavioral state that are both reversed by antidepressant treatment andare associated with an enhancement of adult hippocampal neurogenesis.

We assessed odorant perception, discrimination and memory, using operantdiscrimination paradigms in automated olfactometers. We found analteration of olfactory perception in CORT mice that was reversed byantidepressant treatment. Furthermore, we found a significantcorrelation between the perception threshold of n-butanol and the levelof depression assessed by the splash test.

Moreover, we found an alteration in the discrimination of mixtures ofodorants, more particularly of binary mixtures of monomolecularodorants, in both non-treated and antidepressant drug-treated CORT mice,demonstrating that fine discrimination of odorants is disrupted in thisanimal model of depression and is not rescued by antidepressanttreatment.

Methodology

1. Animals C57BL/6 male mice from Taconic Farms, Inc. (Tornbjergvej 40,DK-4623 Lille Skensved, Denmark) were administered corticosterone (CORT,5 mg/kg/day in drinking water) for one month, to induce ananxiety/depression-like state. Depression-like behavior was checked bythe splash test, the open field test, elevated plus maze and noveltysuppressed feeding.

Then, 29 of these mice were put on a chronic fluoxetine regimen (FLX: 5mg/kg/day in drinking water, with CORT, 5 mg/kg/day, named CORT+FLXmice), as previously described (David et al. 2009, Neuron 62(4):479-493, including Supplemental Data), while 8 mice continued to receivecorticosterone chronically (named CORT mice) [cf. FIG. 1]. Moreover, 8control mice received the vehicle only (named VEHICLE mice) [cf. FIG.1].

2. Behavioral Testing

2.1. Assessment of the Depressive State

Depression related changes include decreased self care, a behavior thatcan be evaluated by the splash test (David et al. 2009, Neuron 62(4):479-493, including Supplemental Data). This test consists in squirting200 microliters of a 10% sucrose solution on the mouse back. Thegrooming latency, frequency and duration are then recorded. About 90% ofC57BL/6 mice demonstrate depression-related signs in response to chroniccorticosterone.

2.2. Assessment of Olfaction

Odorants.

All odorants are monomolecular compounds from Sigma-Aldrich(Sigma-Aldrich Chemie S.a.r.l.; L′Isle d'Abeau Chesnes; 38297Saint-Quentin Fallavier; France), dissolved in water or mineral oil asindicated below.

Automated Olfactometers.

Mice were partially water-deprived by receiving 1-2 mL/day of water forone week and then trained on a “go-out” discrimination task incomputer-controlled eight-channel olfactometers (Lazarini et al. 2009,PlosOne 4(9): e7017). They were trained to respond to the presence of anodorant solution (positive stimulus, S+) diluted in a solvent, likewater or mineral oil, by licking the water delivery tube situated out ofthe odorant sampling port (5 cm distance). They were also trained not torespond on the presentation of another odorant or solvent (negativestimulus, S−). A single stimulus (S+ or S−) was presented at each trial.S+ and S− trials were carried out in random order such that an equalnumber of each type of trial occurred in each series (named block) of 20trials and that one type of trial did not occur more than threeconsecutive times. As described in Lazarini et al. 2009 (PlosOne 4(9):e7017), licking response following an S+ trial and no licking followingan S− trial were scored as correct, and named hit and correct rejectionrespectively [cf. FIG. 2]. In the case of a hit, about 10 μL of waterwere offered as a reward. A licking response following an S− trial andno licking following an S+ trial were scored as error and named falsealarm and miss respectively. Accuracy (percentage of correct responses)was scored for each block of 20 trials [(hits+correctrejections)/20×100]. Olfactory performances were determined usingmonomolecular odorant compounds and binary odorant mixtures. Miceunderwent a session of 8 blocks per day. All odorants were diluted inwater or mineral oil just before the experiments, and theirconcentrations are given as the dilution of the odorant in the saturatorbottles. Mice were initially trained to discriminate betweenisoamylacetate (IAA, dilution 10⁻³ in water, S+) and water (S−).

Odorant Mixture Discrimination Tasks.

Mice were trained to distinguish between 0.1% carvone +(S+) and carvone− (S−) diluted in mineral oil (simple discrimination task). Then,olfactory discrimination performance was determined for two carvonemixture tasks (difficult discrimination task) as follows:

-   -   in the first task:        S+ was a solution of 0.8% carvone + and 0.2% carvone − and        S− was a solution of 0.2% carvone + and 0.8% carvone −;    -   in the second task:        S+ was a solution of 0.6% carvone + and 0.4% carvone − and        S− was a solution of 0.4% carvone + and 0.6% carvone −.

Odorant Detection Threshold.

Mice were trained in the olfactometer to detect successively descendingdecimal concentrations of n-butanol (S+) diluted in water. Eachconcentration was tested daily in 8 blocks of 20 trials. In eachsession, water served as the S−. Mice were given one to two sessions perday (morning, afternoon) with one decimal dilution of the odorant persession. A maximum of 16 blocks per day was allowed (2 sessions of 8blocks). The session stopped at the criterion performance achievement(≧90% of correct response in the block). If the criterion performancewas not achieved in two successive sessions with the same odorantdilution, the preceding dilution was considered as the detectionthreshold.

Results 1. Depressive-Like Behavior

We assessed the grooming behavior of mice using the splash test thatconsists in squirting a sucrose solution on the mouse back and measuringthe latency to groom, the number of grooming sessions as well as totalgrooming duration. This test has been described as a well-validatedindex of a depressed-like state (David et al. 2009, Neuron 62(4):479-493, including Supplemental Data). We observed that mice that wereadministered the chronic treatment with CORT showed a significantlyincreased latency to groom compared to animals that received the vehicle(116.1±17.9 vs 29.1±7.5 s, P<0.001) [cf. FIG. 3A]. Moreover, compared tovehicle-treated animals, grooming duration was decreased in CORT-treatedmice (43.7±5.5 vs 80.5±8.5, P<0.05) [cf. FIG. 3B] as well as groomingfrequency (2.8±0.3 vs 5.9±0.7, P<0.05) [cf. FIG. 3C]. In an interestingmanner, a 2-month fluoxetine treatment (18 mg/kg/day) was able todecrease grooming latency (26.6±4.1 s, P<0.001 vs CORT-treated) [cf.FIG. 3A] and increase grooming duration (92.2±8.9, P<0.05 vsCORT-treated) [cf. FIG. 3B] and frequency (6.1±0.5, P<0.05 vsCORT-treated) [cf. FIG. 3C]. Taken together, these data indicate thatchronic antidepressant treatment is able to attenuate a standardanxiety/depression-like phenotype induced by excess glucocorticoids.

It is worth noting that mice showed depression-related symptoms inresponse to chronic corticosterone when tested in other standardizedbehavioral tests of depression (open field test, elevated plus maze andnovelty suppressed feeding, tail suspended test, forced swim test, datanot shown). Interestingly, chronic fluoxetine administration inCORT-treated mice reversed these symptoms.

2. Olfactory Discrimination and Detection

As shown in FIG. 4A, chronic treatment with CORT alone or CORT andfluoxetine did not alter the ability of mice to discriminate between thetwo similar carvone isoforms in the simple olfactory discriminationtask, since the acquisition rate was similar for all groups. A score of50% corresponds to the success rate expected on the basis of chancealone (dashed line, FIG. 4A). However, in the difficult discriminationtask of carvone mixtures, the performance of CORT animals wassignificantly poorer compared to vehicle-treated animals (P<0.01 for the8/2 vs 2/8 mixture and P<0.05 for the 6/4 vs 4/6 mixture). Chronicadministration of fluoxetine was not able to restore that deficit.Moreover, the results of our olfactory detection test revealed thatchronic CORT treatment induces a significant decrease in the detectionthreshold of around two orders of magnitude (5.7±0.3 vs 7.4±0.4, P<0.01vs vehicle-treated). Interestingly, chronic fluoxetine treatment wasable to restore the threshold in CORT-treated animals (7.3±0.3, P<0.05vs CORT-treated) (FIG. 4B).

3. Correlation Between Depressive State and Olfactory DetectionThreshold

Our results revealed that the degree of certain depressive-like symptomsis significantly correlated to the olfactory threshold score [cf. FIGS.5A and 5B]. More precisely, the olfactory threshold is negativelycorrelated to the latency to groom in the splash test (r²=0.18; P=0.004;n=44) and positively correlated to the number of grooming sessions(r²=0.13; P=0.017; n=43).

4. Long-Term Olfactory Memory

We assessed the ability of CORT animals to remember two odorants learnedone month before. To assess olfactory memory, vehicle, CORT and CORT+FLXmice were trained during 5 consecutive days in order to recall todistinguish between 1% carvone (+) and 1% carvone (−). Carvone (+) wasthe rewarded stimulus and carvone (−) was the unrewarded stimulus. Micewere then retested for the carvone discrimination task at 30 days (t30)following the end of the training session (t0) (FIG. 6A). In this secondsession, no reward was given for correct responses. We assessed thepercentage of correct responses for the three groups during the lastblock of the acquisition period (t0) and during the first block of thememory task performed 30 days later (t30, FIG. 6A). All the three groupsof mice had at least 90% correct responses in the last block of training(acquisition: t0; FIG. 6A), indicating that they were all able toacquire odorant-associated memory. However, a significant difference inperformance was observed between sessions. Performance accuracy wassignificantly lower in the second session for CORT mice when compared tovehicle-treated mice and CORT+FLX animals (% correct response, vehicle:71.25±3.62, CORT: 51.88±2.66, CORT+FLX: 61.35±2.88). Bonferonni post-hoctest: ***: P<0.001 between vehicle and CORT-treated, *: P<0.05 betweenCORT and CORT+FLX). Thus, memory of learned odorants was better retainedover a 30-day period in vehicle-treated compared to CORT mice.CORT-treated animals exhibited a memory deficit that was significantlyattenuated by FLX.

5. Correlation Between Depressive State and Long-Term Olfactory Memory

Our data demonstrated that the degree of certain depressive-likesymptoms is significantly correlated to the olfactory memory score [cf.FIGS. 6B]. Long-term olfactory memory is positively correlated withgrooming frequency in the Splash test. (Pearson's test, r2=0.11;**P=0.03; n=42).

CONCLUSION AND PERSPECTIVES

Our findings in the CORT mice model show that the olfactory perceptionthreshold correlates with the depressive state.

Moreover, we demonstrate that both depressed and antidepressant-treateddepressed mice perform poorly in the task that involves finediscrimination of mixtures of odorants, more particularly of binarymixtures of monomolecular odorants: cf. FIG. 4A.

The experiment, which is above described, can be performed with mixturesof odorants other than the mixtures of carvone + and carvone −, forexample, with:

-   -   mixtures of isoamylacetate and of anethol, e.g., at 8/2 and 2/8        proportions;    -   mixtures of anethol and of eugenol, e.g., at 8/2 and 2/8        proportions.

Odorants are considered safe and are used in food and cosmetic products.

Therefore, the test can easily be implemented in humans (cf. example 2below).

Example 2 Olfactory Test on Humans

The data obtained in the animal model (cf. example 1) allowed us topropose an olfactory test for major depression in humans, based on thediscrimination of mixtures of at least two odorants, more particularlyon the discrimination of mixtures of at least two monomolecularodorants.

Examples of mixtures include (cf. example 1 above):

-   -   mixtures of carvone + and of carvone −, e.g., at 8/2 and 2/8        proportions;    -   mixtures of isoamylacetate and of anethol, e.g., at 8/2 and 2/8        proportions;    -   mixtures of anethol and of eugenol, e.g., at 8/2 and 2/8        proportions.

Odorants can for example be presented in sniffing sticks, such asdescribed in Hummel et al. 1997 (Chem. Senses 22: 39-52) andcommercialized as SNIFFIN' STICKS™ by Burghardt Messtechnik GmbH(Tinsdaler Weg 175, D-2280 Wedel, Germany), e.g., (4 mL) sniffing stickscontaining the odorant mixture in a solvent, such as 2 phenyl ethanol.The mixture discrimination test can optionally be associated with thedetection threshold test (odorant perception test e.g., with n-butanolor phenylethylalcohol; cf. Hummel et al. 1997, Chem. Senses 22: 39-52;cf. Negoias et al. 2010, Neuroscience 169(1): 415-421). For thediscrimination of mixtures, three sticks can be presented to thesubject: two sticks contain the same odorant mixture (e.g., a mixture ofcarvone + and of carvone − at 8/2 proportion in a solvent such as 2phenyl ethanol) and the third tick contains a different associatedodorant mixture (e.g., a mixture of carvone + and of carvone − at 2/8proportion in the same solvent). The subject is requested to indicatethe stick which smells different. For the threshold assessment, twosticks can be presented to the subject: one stick contains the solventand the other stick contains a dilution of n-butanol orphenylethylalcohol (in increasing concentrations, e.g., in increasing2-fold concentrations, e.g., starting from 0.4% vol/vol in propyleneglycol).

For example, the mixture discrimination test can be implemented on apopulation of humans diagnosed with Major Depressive Disorder (MDD),more particularly on:

-   -   MDD humans, who have received an anti-MDD treatment and are        responsive to the treatment,    -   MDD humans, who have received an anti-MDD treatment and are        resistant or non-responsive to the MDD treatment, and    -   MDD patients, who do not have received an anti-MDD treatment        yet.

The mixture discrimination capacity of this population, moreparticularly of each of these three sub-populations, can be compared tothe discrimination capacity of healthy humans, more particularly ofnormosmic healthy humans.

The mixture discrimination test is useful for assessing the degree ofdepression and the response/resistance to antidepressant drugs. Thistest can optionally be associated with the detection threshold test, andis notably useful:

-   -   for the (early) diagnosis of mood disorders, more particularly        Major Depressive Disorder (or Major Depressive Episode),    -   for monitoring or determining the level of efficiency that a        treatment has to treat such a disorder or episode (e.g., SSRI        and/or SNRI treatment) and/or for detecting response or        non-response/resistance to such a treatment.

BIBLIOGRAPHIC REFERENCES Scientific Publications

-   Cain et al. 1988, Laryngoscope 98:83-88;-   Cain 1989, Ear Nose Throat J. 68: 316, 322-328;-   David et al. 2009, Neuron 62(4): 479-493 [including Supplemental    Data];-   Doty et al. 1984, Physiol. Behay. 32: 489-502;-   Doty et al. 1984, Laryngoscope 94 (2Pt1): 176-178-   Doty et al. 1996, Laryngoscope 106 (3Pt1): 353-356,-   Hummel et al. 1997, Chem. Senses 22: 39-52;-   Hummel et al. 2001, Ann. Otol. Rhinol and Laryngol. 110: 976-981;-   Hummel et al. 2007, Eur. Arch. Otorhinolaryngol. 364(3): 237-243;-   Kobal et al. 1996, Rhinology 34: 222-226;-   Kobal et al. 2000, Eur. Arch. Otorhinolaryngol. 257: 205-211;-   Lazarini et al. 2009, PlosOne 4(9): e7017;-   Negoias et al. 2010, Neuroscience 169(1): 415-421;-   Pause et al. 2001, Journal of Psychiatric Research 35: 271-277;-   Pollatos et al. 2007, Journal of Affective Disorders 102: 101-108.

Reference Manuals or Database

-   The “BECK DEPRESSION INVENTORY®” (BDI): Beck, A. T., Steer, R. A., &    Brown, G. K. 1996, “Manual for the Beck Depression Inventory-II”,    San Antonio, Tex.: The Psychological Corporation, U.S.A., more    particularly the BDI-II edition published in 1996;-   <<The Diagnostic and Statistical Manual of Mental Disorders>> (DSM),    edited by the American Psychiatric Association e.g., the DMS-IV-TR    or DSM-V edition;-   the Arctander atlas (Arctander S. “Perfume and flavor chemicals:    (aroma chemicals)”, Allured Publishing Corporation, Carol Stream    Ill., 1994);-   the OdorDB database (Yale Center for Medical Informatics, U.S.A.)    available on    http://senselab.med.yale.edu/odordb/eavObList.aspx?db=5&cl=1.

1. A kit for use in the detection of olfactory discrimination impairmentin a diseased subject, comprising: a first composition comprisingodorants, wherein the odorants of said first composition consist of atleast two different odorants, and, separately or distinctly from saidfirst composition, a second composition comprising odorants, wherein theodorants of said second composition consist of at least two differentodorants, wherein the odorants of said first composition are the samecompounds as the odorants of said second composition, wherein theproportion of the odorants with respect to each other in said firstcomposition is different from their proportion in said secondcomposition, and wherein said second composition is contained induplicate.
 2. The kit of claim 1, wherein the odorants of each of saidfirst and second compositions consists of two different odorants.
 3. Thekit of claim 1 or 2, wherein said first composition and said duplicateof said second composition are each separately contained in an odordispensing device for assessing nasal chemosensory performance.
 4. Thekit of any one of claims 1-3, wherein each of said two differentodorants is a monomolecular compound.
 5. The kit of any one of claims1-4, wherein each of said two different odorants is selected from thegroup consisting of the monomolecular compounds, which emit an odor orscent selected from the group consisting of anise, apple, banana,caramel, chocolate, cinnamon, clove, cocoa, coconut, coffee, cola, dill,eucalyptus, fish, flower, honey, garlic, ginger, grapefruit, grass,lavender, leather, lemon, lilac, lily of the valley, licorice, melon,mint, mushroom, onion, orange, peach, pear, peppermint, pineapple, rose,spearmint, turpentine, raspberry, sesame oil, smoked meat, soy sauce andvanilla.
 6. The kit of any one of claims 1-5, wherein each of said twodifferent odorants is selected from the group consisting of R-carvone,S-carvone, isoamylacetate, anethol, eugenol, 2-phenylethanol, geraniol,linalool, cineole, D-limonene, L-limonene, menthol, and cinnamonaldehyde.
 7. The kit of any one of claims 1-6, which further comprises aplurality of compositions for measuring the olfactory detectionthreshold of a subject, wherein each composition of said pluralitycontains only one odorant, and wherein all the compositions of saidplurality contains the same one odorant and form a serial dilution ofsaid same one odorant.
 8. The kit of any one of claims 1-7, which is foruse in the in vivo diagnosis of a psychiatric disorder or diseaseinvolving mood depression, or for use in the in vivo diagnosis of theseverity of a psychiatric disorder or disease that involves mooddepression, or for use in the treatment of a psychiatric disorder ordisease involving mood depression, or for use in the in vivo diagnosisof response or non-response to a treatment that is intended for treatinga psychiatric disorder or disease involving mood depression, whereinsaid use comprises the sequential smelling or sniffing of said firstcomposition and of said duplicate of said second composition by saidsubject.
 9. The kit of claim 8, wherein said subject scores less than 29according to the BDI-II test.
 10. The kit of claim 8 or 9, wherein saiduse in the in vivo diagnosis of a psychiatric disorder or diseaseinvolving mood depression further comprises determining whether saidsubject has a reduced olfactory discrimination capacity compared to ahealthy and normosmic control subject, a reduced olfactorydiscrimination capacity being indicative of a psychiatric disorder ordisease involving mood depression.
 11. The kit of claim 8 or 9, whereinsaid use in the in vivo diagnosis of the severity of a psychiatricdisorder or disease that involves mood depression further comprisesmeasuring the extent of reduction in olfactory discrimination capacityof said subject, wherein the higher said extent the higher saidseverity.
 12. The kit of claim 8 or 9, wherein said use in the treatmentof a psychiatric disorder or disease involving mood depression furthercomprises selecting a treatment, which increases the olfactorydiscrimination capacity of said subject, and administering said selectedtreatment to said subject.
 13. The kit of claim 8 or 9, wherein said usein the in vivo diagnosis of response or non-response to a treatment thatis intended for treating a psychiatric disorder or disease involvingmood depression further comprises submitting a subject, who has receivedsaid treatment, to said sequential smelling or sniffing, and determiningwhether said treatment increases or decreases the olfactorydiscrimination capacity of said subject, an increased olfactorydiscrimination capacity being indicative of response to said treatment,a reduced or non-significantly different olfactory discriminationcapacity being indicative of non-response to said treatment.
 14. The kitof any one of claim 8, 9, 12 or 13, wherein said treatment comprises theadministration of at least one Selective Serotonin Reuptake Inhibitor(SSRI) and/or at least one Serotonin and Noradrenalin Reuptake Inhibitor(SNRI).
 15. The kit of any one of claims 1-14, wherein said subject isaffected by, or suspected of being affected by a Major DepressiveDisorder (MDD).